Peroxisome Proliferator Activated Receptors (PPAR""s) are members of the nuclear hormone receptor super family, which are ligand-activated transcription factors regulating gene expression. Various subtypes thereof have been identified and cloned. These include PPARxcex1, PPARxcex2 (also known as PPARxcex4), and PPARxcex3. There exist at least two major isoforms of PPARxcex3. While PPARxcex31 is ubiquitously expressed in most tissues, the longer isoform PPARxcex32 is almost exclusively found in adipocytes. In contrast, PPARxcex1 is predominantly expressed in the liver, kidney and heart. PPAR""s modulate a variety of body responses including glucose- and lipid-homeostasis, cell differentiation, inflammatory responses and cardiovascular events.
Diabetes is a disease in which a patient""s ability to control glucose levels in blood is impaired, because he has partially lost the ability to respond properly to the action of insulin. In type II diabetes (T2D), often referred to as non-insulin dependent diabetes mellitus (NIDDM), which afflicts 80-90% of all diabetic patients in developed countries, the Isles of Langerhans in the pancreas still produce insulin. However, the target organs, mainly muscle, liver and adipose tissue, exhibit a profound resistance to insulin stimulation, and the body compensates by producing unphysiologically high levels of insulin. In later stage of disease, however, insulin secretion decreases due to exhaustion of the pancreas. In addition to that T2D is a metabolic-cardiovascular disease sysndrome. Among the comorbidities associated with T2D are for example insulin resistance, dyslipidemia, hypertension, endothelial dysfunction and inflammatory atherosclerosis.
Current first line treatment for diabetes generally involves low fatxe2x80x94and glucosexe2x80x94diet and exercise. However, compliance can be moderate and as the disease progresses, treatment with hypoglycemic drugs, e.g. sulfonylureas or metformin, becomes necessary. A promising new class of drugs has recently been introduced that resensitizes patients to their own insulin (insulin sensitizers), thereby reverting blood glucose and triglyceride levels to normal, and thus abolishing, or at least reducing, the requirement for exogenous insulin. Pioglitazone (Actos(trademark)) and rosiglitazone (Avandia(trademark)) belong to the thiazolidinediones (TZD) class of PPARxcex3-agonists and were the first representatives who had been approved for NIDDM in several countries. These compounds, however, suffer from side effects including rare but severe liver toxicity (as seen with troglitazone), and they increase body weight in humans. Therefore, new, better and more efficacious drugs for the treatment of NIDDM are urgently needed. Recent studies provide evidence that a coagonism on PPARxcex1 and PPARxcex3 would result in compounds with enhanced therapeutic potential, i.e. with an improved lipid profile effect on top of the normalization of glucose- and insulin-levels (Keller and Wahli: Trends Endocrin. Metab. 1993; 4:291-296, Macdonald and Lane: Current Biology Vol.5 pp.618-621 (1995)).
The present invention comprises novel oxazole derivatives, their manufacture and their use as medicaments. In particular, the invention relates to compounds of the formula (I) 
and pharmaceutically acceptable salts and esters thereof.
The present invention comprises compounds of the formula 
and pharmaceutically acceptable salts and esters thereof, wherein
R1 is aryl or heteroaryl;
R2, R3, R4 and R6 are independently selected from the group consisting of hydrogen, hydroxy, lower-alkenyl, halogen, lower-alkyl and lower-alkoxy, wherein at least one of R2, R3, R4 and R6 is not hydrogen, or
R2 and R6 are independently selected from the group consisting of hydrogen, hydroxy, lower-alkenyl, halogen, lower-alkyl and lower-alkoxy, and R3 and R4 are bonded to each other to form a ring together with the carbon atoms to which they are attached, and R3 and R4 together are xe2x80x94CHxe2x95x90CHxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94(CH2)3-5xe2x80x94, xe2x80x94Oxe2x80x94(CH2)2-3xe2x80x94 or xe2x80x94(CH2)2-3xe2x80x94Oxe2x80x94;
R5 is lower-alkoxy, lower-alkenyloxy, 
R7 is hydrogen or lower-alkyl;
R8 is hydrogen or lower-alkyl;
R9 is hydrogen or lower-alkyl;
R10 is aryl;
n is 1, 2 or 3;
wherein the bond between the carbon atom Ca and the carbon atom Cb is a carbon carbon single or double bond.
The novel compounds of the present bind to and activate both, PPARxcex1 and PPARxcex3, simultaneously and very efficiently. Therefore, these compounds combine the anti-gylcemic effect of PPARxcex3 activation with the anti-dyslipidemic effect of PPARxcex1 activation. Consequently, plasma glucose and insulin are reduced (=insulin sensitization), triglycerides lowered and HDL cholesterol increased (=improved lipid profile). In addition, such compounds may also lower LDL cholesterol, decrease blood pressure and counteract inflammatory atherosclerosis. Since multiple facets of the T2D disease syndrome are addressed by PPARxcex1 and xcex3 coagonists, they are expected to have an enhanced therapeutic potential compared to the compounds already known in the art.
The compounds of the present invention further exhibit improved pharmacological properties compared to known compounds.
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term xe2x80x9clowerxe2x80x9d is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
The term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, bromine and iodine.
The term xe2x80x9cprotecting groupxe2x80x9d refers to groups such as e.g. acyl, alkoxycarbonyl, aryloxycarbonyl, silyl, or imine-derivatives, which are used to temporarily block the reactivity of functional groups. Well known protecting groups are e.g. t-butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl or diphenylmethylene which can be used for the protection of amino groups, or lower-alkyl-, xcex2-trimethylsilylethyl- and xcex2-trichloroethyl-esters, which can be used for the protection of carboxy groups.
The term xe2x80x9calkylxe2x80x9d, alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms. Alkyl groups can be substituted e.g. with halogen, hydroxy, lower-alkoxy, lower-alkoxy-carbonyl, NH2, N(H, lower-alkyl) and/or N(lower-alkyl)2.
The term xe2x80x9clower-alkylxe2x80x9d, alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like. A lower-alkyl group may have a substitution pattern as described earlier in connection with the term xe2x80x9calkylxe2x80x9d.
The term xe2x80x9calkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Oxe2x80x94, wherein Rxe2x80x2 is alkyl. The term xe2x80x9clower-alkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Oxe2x80x94, wherein Rxe2x80x2 is lower-alkyl. Examples of lower-alkoxy groups are e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy.
The term xe2x80x9clower-alkenylxe2x80x9d, alone or in combination signifies a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 8, preferably up to 6, particularly preferred up to 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl. A preferred example is 2-propenyl.
The term xe2x80x9clower-alkenyloxyxe2x80x9d means a group Rxe2x80x3xe2x80x94Oxe2x80x94, wherein Rxe2x80x3 is lower-alkenyl. Examples of lower-alkenyloxy groups are butenyloxy, particularly but-3-enyloxy.
The term xe2x80x9carylxe2x80x9d relates to the phenyl or naphthyl group, preferably the phenyl group, which can optionally be mono- or multiply-substituted, particularly mono- or di-substituted by halogen, hydroxy, CN, CF3, NO2, NH2, N(H, lower-alkyl), N(lower-alkyl)2, carboxy, aminocarbonyl, lower-alkyl, lower-alkoxy, aryl and/or aryloxy. Preferred substituents are halogen, CF3, lower-alkyl and/or lower-alkoxy.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic 5- or 6-membered ring which can comprise 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, or pyrrolyl. The term xe2x80x9cheteroarylxe2x80x9d further refers to bicyclic aromatic groups comprising two 5- or 6-membered rings, in which one or both rings can contain 1, 2 or 3 atoms selected from nitrogen, oxygen or sulphur such as e.g. indole or quinoline, or partially hydrogenated bicyclic aromatic groups such as e.g. indolinyl. A heteroaryl group may have a substitution pattern as described earlier in connection with the term xe2x80x9carylxe2x80x9d. Preferred heteroaryl groups are e.g. thienyl and furyl which can optionally be substituted as described above, preferably with halogen, CF3, lower-alkyl and/or lower-alkoxy.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms. Preferred salts with acids are formates, maleates, citrates, hydrochlorides, hydrobromides and methanesulfonic acid salts. The compounds of formula I further form salts with pharmaceutically acceptable bases such as alkali salts, e.g. Na- and K-salts, alkaline earth salts, e.g. Ca- and Mg-salts, and ammonium or substituted ammonium salts, such as e.g. trimethylammonium salts. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d also relates to such salts.
The compounds of formula I can also be solvated, e.g. hydrated. The solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration). The term pharmaceutically acceptable salts also includes pharmaceutically acceptable solvates.
The term pharmaceutically acceptable esters of the compounds of formula I means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.
In more detail, for example, the COOH group of compounds according to formula I can be esterified. Alkyl and aralkyl esters are examples of suitable esters. The methyl, ethyl, propyl, butyl and benzyl esters are preferred esters. The methyl and ethyl esters are especially preferred. Further examples of pharmaceutically usable esters are compounds of formula I, wherein e.g. a hydroxy group is esterified. Examples of such esters are formate, acetate, propionate, butyrate, isobutyrate, valerate, 2-methylbutyrate, isovalerate and N,N-dimethylaminoacetate. Preferred esters are acetate and N,N-dimethylaminoacetate.
Preferred compounds of formula I are compounds according to formula Ib 
wherein
R1 is aryl or heteroaryl,
R2, R3 and R4 independently from each other are hydrogen, halogen, lower-alkyl, or lower-alkoxy, wherein at least one of R2, R3 and R4 is not hydrogen, or
R3 and R4 are bonded to each other to form a ring together with the carbon atoms to which they are attached, and R3 and R4 together are xe2x80x94CHxe2x95x90CHxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, or xe2x80x94(CH2)3-5xe2x80x94, and R2 is as defined above,
R5 is lower-alkoxy or 
xe2x80x83and pharmaceutically acceptable salts thereof.
In a particularly preferred embodiment, the present invention relates to compounds of formula (I), characterized by formula (Ibb) 
wherein R1, R2, R3, R4 and R5 are as defined above, and pharmaceutically acceptable salts thereof Formula (Ibb) means that the asymmetric carbon atom C* has the S configuration according to the Cahn-Ingold-Prelog-Convention.
In addition, compounds as defined above in which R1 is phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, CF3, lower-alkyl and lower-alkoxy are preferred, with unsubstituted phenyl being particularly preferred. Furthermore, compounds as defined above in which R1 is thienyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, CF3, lower-alkyl and lower-alkoxy are preferred, with unsubstituted thienyl being particularly preferred.
Compounds of formula (I), wherein R3 and R4 are bonded to each other to form a ring together with the carbon atoms to which they are attached, and R3 and R4 together are xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, and R2 and R6 are hydrogen, are also preferred. Such compounds consequently comprise the following moiety 
Further, compounds of formula (I), wherein R3 and R4 are bonded to each other to form a ring together with the carbon atoms to which they are attached, and R3 and R4 together are xe2x80x94CHxe2x95x90CHxe2x80x94Sxe2x80x94, and R2 and R6 are hydrogen, are preferred. Such compounds consequently comprise the following moiety 
In addition, compounds as defined above, wherein R2, R3 and R4 independently from each other are hydrogen or lower-alkyl are preferred, with those wherein R2 and R3 are methyl and R4 is hydrogen being particularly preferred. Other particularly preferred compounds of formula (I) are those wherein R2 is methyl and R3 and R4 are hydrogen. Further particularly preferred compounds of formula (I) are those wherein R4 is methyl and R2 and R3 are hydrogen. Particularly preferred are those compounds of formula I, wherein R6 is hydrogen.
Compounds of formula (I) wherein R5 is lower-alkoxy represent a preferred embodiment of the present invention, with those compounds wherein R5 is methoxy, ethoxy, propoxy, butoxy, isobutoxy, or hexyloxy representing a particularly preferred embodiment. Other preferred compounds are those wherein R5 is 
Preferred are compounds according to formula I and the pharmaceutically acceptable salts thereof. Particularly preferred are compounds of formula I.
A preferred aspect of the present invention are compounds according to formula I, wherein
R2, R3 and R4 independently from each other are hydrogen, halogen, lower-alkyl or lower-alkoxy, wherein at least one of R2, R3 and R4 is not hydrogen, or
R3 and R4 are bonded to each other to form a ring together with the carbon atoms to which they are attached, and R3 and R4 together are xe2x80x94CHxe2x95x90CHxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94(CH2)3-5xe2x80x94 and, wherein R2 is as defined above;
R5 is lower-alkoxy or 
R6 is hydrogen;
R7 is methyl;
n is 2;
wherein the bond between the carbon atom Ca and the carbon atom Cb is a carbon carbon single bond;
and pharmaceutically acceptable salts thereof.
Preferred are compounds of formula I, wherein R1 is phenyl or thienyl, optionally substituted with one or more, particularly one to three substituents, independently selected from trifluoromethyl, aryl, alkyl, alkoxy and halogen. Particularly preferred are compounds according to formula I, wherein R1 is phenyl or phenyl substituted with 1 to 3 substituents independently selected from alkoxy and trifluoromethyl.
Another preferred aspect of the present invention are compounds of formula I, wherein R2, R3, R4 and R6 independently from each other are hydrogen, hydroxy, lower-alkyl or lower-alkoxy, wherein at least one of R2, R3, R4 and R6 is not hydrogen, or R3 and R4 are bonded to each other to form a ring together with the carbon atoms to which they are attached, and R3 and R4 together are xe2x80x94CHxe2x95x90CHxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, and, wherein R2 and R6 are as defined above.
Particularly preferred are compounds according to formula I, wherein R2, R3, R4 and R6 independently from each other are hydrogen, hydroxy, lower-alkyl or lower-alkoxy and wherein at least one of R2, R3, R4 and R6 is not hydrogen. Further particularly preferred are compounds of formula I, wherein R3 and R4 are bonded to each other to form a ring together with the carbon atoms to which they are attached, and R3 and R4 together are xe2x80x94CHxe2x95x90CHxe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, and, wherein R2 and R6 are defined as before. Likewise particularly preferred are those compounds of formula I, wherein R6 is hydrogen.
Further preferred are compounds according to formula I, wherein R2 and R6 are hydrogen and R3 and R4 are bonded to each other to form a ring together with the carbon atoms to which they are attached, and R3 and R4 together are xe2x80x94CHxe2x95x90CHxe2x80x94Sxe2x80x94 or xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94.
Particularly preferred are compounds according to formula I, wherein R3 and R4 together are xe2x80x94CHxe2x95x90CHxe2x80x94Sxe2x80x94. Such compounds consequently are of the following formula 
Another preferred aspect of the present invention are compounds according to formula I, wherein R5 is lower-alkoxy or 
Particularly preferred are those compounds of formula I, wherein R5 is lower-alkoxy. Further particularly preferred are compounds according to formula I, wherein R5 is methoxy, ethoxy or propoxy.
A further preferred aspect of the present application are compounds of formula I, wherein R7 is alkyl. Particularly preferred are those compounds according to formula I, wherein R7 is methyl.
Also preferred are compounds of formula I, wherein R8 is lower-alkyl particularly methyl.
Also preferred are compounds of formula I, wherein R9 is hydrogen. Further preferred are compounds of formula I, wherein R9 is lower-alkyl.
Further preferred are compounds of formula I, wherein R10 is phenyl or phenyl substituted with lower-alkyl. Particularly preferred are those compounds of formula I, wherein R10 is phenyl.
Preferred are compounds of formula I, wherein n is 1. Further preferred are compounds of formula I, wherein n is 2 or 3. Particularly preferred are those compounds of formula I, wherein n is 2.
The compounds of formula I can contain several asymmetric centres and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbens or eluant).
The term xe2x80x9casymmetric carbon atomxe2x80x9d (C*) means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog-Convention the asymmetric carbon atom can be of the xe2x80x9cRxe2x80x9d or xe2x80x9cSxe2x80x9d configuration.
Preferred are chiral compounds of formula (I), characterized by formula (Ia) 
wherein R1, R2, R3, R4, R5, R6, R7 and n are defined as before. Formula (Ia) means that the asymmetric carbon atom C* 
is of the S configuration. Particularly preferred are compounds according to formula (Ia), wherein R1, R2, R3, R4, R6, R7 and n are defined as before and, wherein R5 means lower-alkoxy.
Preferred are compounds of formula I, wherein the bond between the carbon atom Ca and the carbon atom Cb is a carbon carbon double bond (either E- or Z-configuration according to the Cahn-Ingold-Prelog-Convention). Consequently, those compounds are of the following formula (Ic) 
Preferred is the E-configuration. Particularly preferred is the Z-configuration.
Further, particularly preferred are compounds of formula I, wherein the bond between the carbon atom Ca and the carbon atom Cb is a carbon carbon single bond. Consequently, those compounds are of the following formula (Id) 
Preferred compounds of general formula (I) are those selected from the following group:
1. 2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid;
2. 2-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7yl }-propionic acid;
3. 3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-2-propoxy-propionic acid;
4. 2-Butoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid;
5. 2-Isobutoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid;
6. 2-Hexyloxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo [b]thiophen-7-yl}-propionic acid;
7. 2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid;
8. 2-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid;
9. 3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-propoxy -propionic acid;
10. 2-Butoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid;
11. (S)-2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid;
12. (S)-2-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid;
13. (S)-2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid;
14. (S)-2-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid;
15. 2-(2-Benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid;
16. 2-(2-Benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid;
17. 3-{3,5-Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-propionic acid;
18. 2-Ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
19. 2-(2-Benzoyl-phenylamino)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
20. 2-(2-Benzoyl-phenylamino)-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
21. (S)-2-Methoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-propionic acid;
22. (S)-2-Ethoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-propionic acid;
23. (S)-2-Methoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid;
24. (S)-2-Ethoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid;
25. (S)-3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-ethoxy-propionic acid;
26. (S)-3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-propoxy-propionic acid;
27. (S)-3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-2-propoxy-propionic acid;
28. (S)-3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-methoxy-propionic acid;
29. (S)-3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-(2,2,2-trifluoro-ethoxy)-propionic acid;
30. (S)-3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-2-ethoxy-propionic acid;
31. (S)-3-(4-{2-[2-(4-Isopropyl-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-methoxy-propionic acid;
32. (S)-3-(4-{2-[2-(4-Isopropyl-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-(2,2,2-trifluoro-ethoxy)-propionic acid;
33. (S)-3-(4-{2-[2-(3,5-Dimethyl-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-methoxy-propionic acid;
34. (S)-3-(4-{2-[2-(3,5-Dimethoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-methoxy-propionic acid;
35. (S)-3-(4-{2-[2-(3,5-Dimethyl-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-methoxy-propionic acid;
36. [rac]-3-(4-{2-[2-(3,5-Dichloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-methoxy-propionic acid;
37. [rac]-3-(4-{2-[2-(3,5-Difluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-methoxy-propionic acid;
38. [rac]-2-Butoxy-3-(4-{2-[2-(3,5-difluoro-phenyl)-5-methyl-oxazol-4-yl}-benzo[b]thiophen-7-yl)-propionic acid;
39. [rac]-2-Butoxy-3-(4-{2-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid;
40. [rac]-2-Butoxy-3-(4-{2-[2-(3,5-dimethyl-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid;
41. [rac]-3-(4-{2-[2-(3,5-Difluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-ethoxy-propionic acid;
42. [rac]-2-Methoxy-3-(4-{3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-propionic acid;
43. [rac]-3-(4-{3-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-2-methoxy-propionic acid;
44. [rac]-2-Methoxy-3-(4-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-propoxy}-benzo[b]thiophen-7-yl)-propionic acid;
45. [rac]-2-Ethoxy-3-(4-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propoxy}-benzo[b]thiophen-7-yl)-propionic acid;
46. [rac]-3-(4-{3-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-2-isopropoxy-propionic acid;
47. (S)-2-Methoxy-3-(4-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-propionic acid;
48. [rac]-3-(4-{3-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-benzo[b]thiophen-7-yl)-2-methoxy-propionic acid;
49. [rac]-2-Ethoxy-3-(4-{3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-propionic acid;
50. [rac]-2-Ethoxy-3-(4-{3-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-propionic acid;
51. [rac]-3-(4-{3-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-2-ethoxy-propionic acid;
52. [rac]-3-(4-{3-[2-(4-Isopropyl-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-2-methoxy-propionic acid;
53. [rac]-3-(4-{2-[2-(3,5-Dimethyl-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-ethoxy-propionic acid;
54. [rac]-3-(4-{2-[2-(3,5-Dimethoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-ethoxy-propionic acid;
55. [rac]-2-Ethoxy-3-(4-{3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-benzo[b]thiophen-7-yl)-propionic acid;
56. [rac]-2-Methoxy-3-(4-{3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-benzo[b]thiophen-7-yl)-propionic acid;
57. [rac]-2-Ethoxy-3-(4-{3-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-benzo[b]thiophen-7-yl)-propionic acid;
58. [rac]-3-(4-{3-[2-(4-Isopropyl-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-benzo[b]thiophen-7-yl)-2-methoxy-propionic acid;
59. [rac]-3-(4-{3-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-benzo[b]thiophen-7-yl)-2-ethoxy-propionic acid;
60. [rac]-3-(4-{3-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-benzo[b]thiophen-7-yl)-2-methoxy-propionic acid
61. [rac]-2-Ethoxy-3-(4-{3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-naphthalen-1-yl) -propionic acid;
62. [rac]-2-Ethoxy-3-(4-{3-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-propionic acid;
63. [rac]-3-(4-{3-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-2-ethoxy-propionic acid;
64. [rac]-2-Ethoxy-3-(4-{2-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid;
65. (S)-2-But-3-enyloxy-3-(4-{2-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo [b]thiophen-7-yl)-propionic acid;
66. [rac]-3-(4-{2-[2-(4-Isopropyl-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-propoxy-propionic acid;
67. [rac]-2-Ethoxy-3-(4-{2-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-propionic acid;
68. [rac]-3-(4-{2-[2-(3,5-Dimethoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-isopropoxy-propionic acid;
69. (S)-3-(4-{2-[2-(3,5-Dimethoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-isopropoxy-propionic acid;
70. [rac]-3-(4-{3-[2-(4-Isopropyl-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-benzo[b]thiophen-7-yl)-2-propoxy-propionic acid;
71. [rac]-3-(4-{2-[2-(3,5-Dimethoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-ethoxy-propionic acid;
72. [rac]-3-(4-{2-[2-(3,5-Dimethoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-propoxy-propionic acid;
73. [rac]-3-(4-{2-[2-(3,5-Dimethoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-isopropoxy-propionic acid;
74. [rac]-2-Isopropoxy-3-(4-{2-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-propionic acid;
75. 2Z-Ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid;
76. [rac]-2-Ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
77. 2(S)-Ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
78. 2(R)-Ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
79. 3-{2,3-Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2Z-ethoxy-acrylic acid;
80. [rac]-3-{2,3-Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl]-2-ethoxy-propionic acid;
81. 3-{2,6-Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2Z-ethoxy-acrylic acid;
82. [rac]-3-{2,6-Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-propionic acid;
83. 2Z-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzofuran-7-yl}-acrylic acid;
84. 2E-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzofuran-7-yl}-acrylic acid;
85. [rac]-2-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzofuran-7-yl}-propionic acid;
86. [rac]-2-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2,3-dihydro-benzofuran-7-yl}-propionic acid;
87. 2Z-Ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzofuran-4-yl}-acrylic acid;
88. 2E-Ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzofuran-4-yl}-acrylic acid;
89. [rac]-2-Ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzofuran-4-yl}-propionic acid;
90. [rac]-2-Ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2,3-dihydro-benzofuran-4-yl}-propionic acid;
91. [rac]-2-Ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-yl}-propionic acid;
92. [rac]-2-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid;
93. [rac]-3-(4-{2-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-2-ethoxy-propionic acid;
94. [rac]-2-Ethoxy-3-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzob]thiophen-7-yl)-propionic acid;
95. [rac]-2-Ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid;
96. [rac]-2-Ethoxy-3-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid;
97. [rac]-2-Ethoxy-3-(4-{2-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy }-benzo[b]thiophen-7-yl)-propionic acid;
98. (S)-2-Methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionic acid;
99. 2Z-Ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-yl}-acrylic acid; (S)-2-Methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-yl}-propionic acid;
100. [rac]-3-(4-{2-[2-(2-Ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-methoxy-propionic acid;
101. [rac]-2-Methoxy-3-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-propionic acid;
102. 2Z-Ethoxy-3-{7-[2-(5-methyl-2-phenyl- oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-acrylic acid;
103. [rac]-2-Ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionic acid;
104. [rac]-2-[1-Methyl-3-oxo-3-phenyl-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid;
105. [rac]-2-[1-Methyl-3-oxo-3-(4-trifluoromethyl-phenyl)-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid;
106. [rac]-3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-2-[3-oxo-3-phenyl-1-trifluoromethyl-(Z)-propenylamino]-propionic acid;
107. [rac]-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid;
108. [rac]-2-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-propionic acid;
109. [rac]-2-Ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid;
110. [rac]-2-Ethoxy-3-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid;
111. [rac]-2-Ethoxy-3-(4-{3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid;
112. [rac]-2-Ethoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid;
113. [rac]-2-Methoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
114. [rac]-2-Methoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
115. [rac]-Lithium 2-ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionate
116. [rac]-3-{3,5-Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methoxy-propionic acid;
117. [rac]-3-{2-Hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methoxy-propionic acid;
118. [rac]-3-{3-Methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(1-methyl-3-oxo-3-phenyl-(Z)-propenylamino)-propionic acid;
119. [rac]-2-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzofuran-7-yl]-propionic acid;
120. [rac]-2-Ethoxy-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzofuran-7-yl]-propionic acid;
121. [rac]-2-Ethoxy-3-{4-[2-(4-ethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-propionic acid;
122. [rac]-3-{4-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-2-ethoxy-propionic acid;
123. [rac]-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-propionic acid;
124. [rac]-2-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2,3-dihydro-benzofuran-7-yl]-propionic acid;
125. [rac]-2-Ethoxy-3-{4-[2-(4-ethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,3-dihydro-benzofuran-7-yl}-propionic acid;
126. [rac]-3-{4-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,3-dihydro-benzofuran-7-yl}-2-ethoxy-propionic acid;
127. [rac]-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,3-dihydro-benzofuran-7-yl}-propionic acid;
128. [rac]-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid;
129. [rac]-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-propionic acid;
130. [rac]-2-Ethoxy-3-{4-[2-(4-ethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid;
131. [rac]-3-{4-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid;
132. [rac]-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid;
133. (S)-2-But-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
134. 3-{3,5-Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2Z-ethoxy-acrylic acid;
135. [rac]-3-{4-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-2-ethoxy-propionic acid;
136. [rac]-3-{4-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid;
137. [rac]-3-{4-[2-(3,5-Dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-2-ethoxy-propionic acid;
138. 2Z-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylic acid;
139. [rac]-2-Ethoxy-3-[3-methyl-4-(2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid;
140. (S)-3-{3,5-Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-propoxy-propionic acid;
141. 2Z-But-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid;
142. 2E-But-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid;
143. [rac]-3-{4-[2-(2-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid;
144. [rac]-3-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid;
145. [rac]-2-Ethoxy-3-{2-methyl-4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-phenyl}-propionic acid;
146. [rac]-2-Ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid;
147. [rac]-2-Ethoxy-3-{4-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid;
148. [rac]-3-(4-{2-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-2-ethoxy-propionic acid;
149. [rac]-2-Ethoxy-3-[4-(5- methyl-2-phenyl-oxazol-4-ylmethoxy)-naphthalen-1-yl]-propionic acid;
150. [rac]-2-Ethoxy-3-[7-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzo[b]thiophen-4-yl]-propionic acid;
151. [rac]-2-Ethoxy-3-{7-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzo[b]thiophen-4-yl}-propionic acid;
152. [rac]-2-Ethoxy-3-(7-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-4-yl)-propionic acid;
153. [rac]-3-(7-{2-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[]thiophen-4-yl)-2-ethoxy-propionic acid;
154. [rac]-3-{7-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzo[b]thiophen-4-yl}-2-ethoxy-propionic acid;
155. (S)-2-Ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
156. (2S)-3-{3,5-Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-propionic acid;
157. [rac]-2-Ethoxy-3-{3-fluoro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
158. [rac]-2-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3-propyl-phenyl}-propionic acid;
159. (2S)-2-Ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
160. (2S)-2-Ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
161. [rac]-2-Isopropoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid;
162. (S)-2-Isopropoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid;
163. [rac]-3-{3-Allyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-ethoxy-propionic acid.
Particularly preferred compounds of formula I are selected from the following group:
2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid;
3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-2-propoxy-propionic acid;
(S)-2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid;
(S)-3-(4-{2-[2-(3,5-Dimethoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl) -2-methoxy-propionic acid;
(S)-2-Methoxy-3-(4-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-propionic acid;
2Z- Ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid;
2(S)-Ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid;
2Z-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzofuran-7-yl}-acrylic acid;
[rac]-2-[1-Methyl-3-oxo-3-phenyl-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid;
[rac]-3-{2-Hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methoxy-propionic acid;
[rac]-3-{3-Methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(1-methyl-3-oxo-3-phenyl-(Z)-propenylamino)-propionic acid;
[rac]-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid;
[rac]-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid;
(2S)-3-{3,5-Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-propionic acid; and
(2S)-2-Ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid.
Further particularly preferred is (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid and pharmaceutically acceptable salts and esters thereof. Most preferred is (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid.
Compounds of formula (I) can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers or as racemates. The invention embraces all of these forms.
It will be appreciated, that the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
A further aspect of the present invention is the process for the manufacture of compounds of formula I, comprising the deprotection of a compound of formula II 
wherein R1, R2, R3, R4, R5, R6, R7 and n are as defined as before and PG is a protecting group.
The present invention also relates to a process for the manufacture of compounds of formula (I) as defined above, which process comprises removing a protecting group in a compound of formula (IIa) 
wherein R1, R2, R3, R4 and R5 are as defined above and PG is a protecting group, and optionally converting the resulting compound of formula (I) to a pharmaceutically acceptable salt.
Possible protecting groups PG in compounds of formula (II) are e.g. lower-alkyl-, xcex2-trimethylsilylethyl- and xcex2-trichloroethyl-esters, which can be used for the protection of the corresponding carboxy group. Lower-alkyl-ester protecting groups can be removed in the presence of a base such as e.g. LiOH or NaOH in a solvent such as e.g. H2O, ethanol, tetrahydrofuran, or dioxan, or in a mixture of such solvents, e.g. in a temperature range of 10-50xc2x0 C. The xcex2-trichloroethyl-ester protecting group can be removed in the presence of Zn in acetic acid, e.g. in a temperature range of 10-50xc2x0 C. The xcex2-trimethylsilylethyl-ester protecting group can be removed in the presence of tetrabutylammonium fluoride in tetrahydrofuran, e.g. in a temperature range of 20-65xc2x0 C. Methods for converting a compound of formula (I) as defined above to a pharmaceutically acceptable salt are known in the art.
The invention further relates to compounds of formula (I) as defined above, when manufactured according to a process as defined above.
As described above, the compounds of formula (I) of the present invention can be used as medicaments for the treatment and/or prophylaxis of diseases which are modulated by PPARxcex1 and/or PPARxcex3 agonists. Examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, elevated blood pressure, increased lipid and cholesterol levels, atherosclerotic diseases and metabolic syndrome. The use as medicament for the treatment and/or prophylaxis of non-insulin dependent diabetes mellitus is preferred.
The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
Further, the invention relates to compounds as defined above for use as therapeutic active substances, particularly as therapeutic active substances for the treatment and/or prophylaxis of diseases which are modulated by PPARxcex1 and/or PPARxcex3 agonists. Examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, elevated blood pressure, increased lipid and cholesterol levels, atherosclerotic diseases and metabolic syndrome, preferably non-insulin dependent diabetes mellitus.
In another embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases which are modulated by PPARxcex1 and/or PPARxcex3 agonists, which method comprises administering a compound of formula I to a human or animal. Preferred examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, elevated blood pressure, increased lipid and cholesterol levels, atherosclerotic diseases and metabolic syndrome, preferably for the treatment and/or prophylaxis of non-insulin dependent diabetes mellitus.
The invention further relates to the use of compounds as defined above for the treatment and/or prophylaxis of diseases which are modulated by PPARxcex1 and/or PPARxcex3 agonists. Preferred examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, elevated blood pressure, increased lipid and cholesterol levels, atherosclerotic diseases and metabolic syndrome, preferably non-insulin dependent diabetes mellitus.
In addition, the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment and/or prophylaxis of diseases which are modulated by PPARxcex1 and/or PPARxcex3 agonists. Preferred examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, elevated blood pressure, increased lipid and cholesterol levels, atherosclerotic diseases and metabolic syndrome, preferably non-insulin dependent diabetes mellitus. Such medicaments comprise a compound as defined above.
The compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art.
Starting materials are either commercially available or can be prepared by methods analogous to the methods given below or in the examples or by methods known in the art, e.g. from WO 94/27995, WO 98/42704 and EP 1078923 and references cited therein and from references cited in the following text.
Racemates of compounds of formula (I), (compounds 11 in scheme 1, compounds 8 in scheme 2, compounds rac-6 in scheme 3) as well as achiral olefinic compounds of formula (I) with alkoxy substituents R5 (compounds 11 in scheme 1) can e.g. be synthesized according to the methods depicted in scheme 1, scheme 2 and scheme 3 or by analogous methods.
Racemates and optically pure analogues of compounds of formula (I) with amino substituents R5 (compounds 6 in scheme 3) can e.g. be synthesized according to the methods depicted in scheme 3 or by analogous methods.
Homochiral compounds of formula (I) with alkoxy substituents R5, (compound 8 in scheme 4) can be prepared according to the method depicted in scheme 4 or by analogous methods. 
Phenols 1 and/or aldehydes 6 are known or can be synthesized by methods known in the art. Examples for possible syntheses of such phenols and aldehydes are given in schemes 5-10. Aryl-oxazole compounds 2 (prepared as outlined in schemes 11-12) are condensed with phenols 1 or aldehydes 6 according to well known procedures: if R12 represents a hydroxy group e.g. via a Mitsunobu-reaction, with triphenylphosphine and di-tert-butyl-, diisopropyl- or diethyl-azodicarboxylate as reagents; the Mitsunobu-reaction is preferably carried out in a solvent like toluene or tetrahydrofuran at ambient temperature. Alternatively, if R12 represents a halide, mesylate or tosylate moiety, the aryl-oxazole compounds 2 can be reacted with phenols 1 or aldehydes 6 in solvents like N,N-dimethylformamide, acetone or methyl-ethyl ketone in the presence of a weak base like cesium or potassium carbonate at a temperature ranging from room temperature to 140xc2x0 C., preferably around 50xc2x0 C.; thus ether compounds 3 or aldehydes 5 are obtained (step a). The former are then subjected to bromomethylation, e.g. by treatment with trioxane and HBr, preferably 62% aq. HBr, in an inert solvent, preferably dichloromethane, preferably at 0xc2x0 C. giving a highly reactive, often quite unstable electrophile 4 (step b). The electrophile 4 is suitable to alkylate an enolate of alkoxy-acetic acid esters 7 (R11=lower alkyl), preferably the lithium-enolate, prepared at xe2x88x9278xc2x0 C. by treatment of 7 with a strong, non-nucleophilic base like lithium diisopropylamide in an inert solvent like tetrahydrofuran. To increase the reactivity of the enolate nucleophile, the reaction is preferably performed in the presence of a cosolvent like hexamethylphosphoramide (HMPA) or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) to give esters 9 (step d). Alternatively, aldehyde compounds 5, which are also available by Vilsmeier formylation or through formylation with dichloromethyl methyl ether in the presence of titanium tetrachloride, preferably in dichloromethane at temperatures between xe2x88x9278xc2x0 C. and the reflux temperature of the solvent (step c), are reacted with an enolate of alkoxy-acetic acid esters 7 (preferably the lithium-enolate, prepared at xe2x88x9278xc2x0 C. by treatment of 7 with a strong, non-nucleophilic base like lithium diisopropylamide in an inert solvent like tetrahydrofuran), preferably at temperatures around xe2x88x9278xc2x0 C., in solvents like tetrahydrofuran giving the aldol product 8 as a mixture of diasteromers (step e). Removal of the benzylic hydroxy group in 8 with a reducing agent like e.g. triethylsilane in the presence of a Lewis acid, like boron-trifluoride, or a protic acid, like trifluoroacetic acid, in a suitable solvent like trifluoroacetic acid itself or dichloromethane between 0xc2x0 C. and 60xc2x0 C. gives racemic esters 9 (step f). Alternatively, aldehydes 5 can be reacted with a Wittig salt such as (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride or (methoxy-methoxycarbonyl-methyl)-triphenyl-phosphonium bromide in solvents like isopropanol, dichloromethane or tetrahydrofuran or mixtures thereof in the presence of a base like potassium carbonate or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably between 0xc2x0 C. and the reflux temperature of the solvents, giving acrylic esters 10 as E and/or Z isomers (step g). Hydrogenation of acrylic esters 10 using palladium on charcoal as catalyst, preferably at room temperature and 1 atm. pressure of hydrogen, in solvents like methanol, tetrahydrofuran, acetic acid, dichloromethane and mixtures thereof, affords racemic esters 9 (step h). Hydrogenation of compounds in which R3-R4 together with the attached benzene ring form a benzofuran moiety can be performed using extended reaction times to provide the corresponding benzo-dihydrofuran analogues. In compounds, in which R3-R4 together with the attached benzene ring form a benzothiophene moiety, the double bond reduction is preferably performed with magnesium in solvent mixtures like tetrahydrofuran/methanol between room temperature and the reflux temperature of the solvents. The esters 9 and 10 can optionally be hydrolyzed according to standard procedures, e.g. by treatment with an alkali hydroxide like LiOH or NaOH in a polar solvent mixture like tetrahydrofuran/ethanol/water leading to carboxylic acids 11 (step i). 
Aldehydes 3 (optionally carrying a protective function) can be obtained from phenols 1 or protected phenols 2 (introduction of protective function, preferably a benzyl ether: step a), by known formylation reactions such as the Vilsmeier formylation or formylation by dichloromethyl methyl ether in the presence of titanium tetrachloride, preferably in dichloromethane at temperatures between xe2x88x9278xc2x0 C. and the reflux temperature of the solvent (step b). Aldehydes 3 can then be reacted with a Wittig salt such as (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride or (methoxy-methoxycarbonyl-methyl)-triphenyl-phosphonium bromide in solvents like isopropanol, dichloromethane or tetrahydrofuran or mixtures thereof in the presence of a base like potassium carbonate or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably between 0xc2x0 C. and the reflux temperature of the solvents, giving acrylic esters 4 as E and/or Z isomers (step c). Catalytic hydrogenation of acrylic esters 4 with palladium on charcoal in solvents like methanol, ethanol or tetrahydrofuran leads to phenols 5 (step d). In cases, where R3 and R4 form together with the attached benzene ring a benzothiophene or a benzofuran moiety, a two step procedure is preferred: in a first reaction, the double bond of the acrylic ester moiety is reduced using magnesium in a mixture of methanol and tetrahydrofuran between room temperature and the reflux temperature of the solvents. Subsequently, the protecting group like a benzyl ether is cleaved, e.g. by using dimethyl sulfide and boron trifluoride diethyl etherate in a solvent like dichloromethane between room temperature and the reflux temperature of the solvent to give phenolic compounds 5. Those are then condensed with aryloxazoles 6 to ether compounds 7 (step e) using well known procedures described in scheme 1 for the condensation of phenols 1 or 4-hydroxy-benzaldehydes 6 with arlyoxazoles. Esters 7 can optionally be saponified to acids 8 using standard conditions of alkaline hydrolysis (step f) 
Alpha amino esters 4 may be prepared by i) transformation of a protected glycine ester, preferably N-(diphenylmethylene) glycine ethyl ester, into a corresponding enolate, preferably the lithium-enolate, preferably at xe2x88x9278xc2x0 C., by treatment with a strong, non-nucleophilic base like lithium diisopropylamide in an inert solvent like tetrahydrofuran; ii) reaction of the thus formed enolate with benzylbromides 1 (compounds 4 in scheme 1), preferably between xe2x88x9278xc2x0 C. and room temperature, preferably in the presence of a cosolvent which increases the reactivity of the nucleophile like hexamethylphosphoramide (HMPA) or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU); iii) hydrolysis of the imine intermediate with an acid, e.g. diluted hydrogen chloride solution (step a). Alternatively, alpha amino esters 4 can be prepared from aldehydes 2 (compounds 5 in scheme 1), by i) condensation with a suitable phosphonoglycine ester e.g. N-(benzyloxycarbonyl)-alpha-phosphonoglycine trimethyl ester in solvents like dichloromethane or tetrahydrofuran in the presence of a base like Huenig""s base between room temperature and the reflux temperature of the solvent leading to enamine carbamates 3; ii) catalytic hydrogenation and deprotection of enamine carbamates 3 using e.g. hydrogen in the presence of palladium on charcoal in solvents like ethyl acetate, tetrahydrofuran or methanol (steps b, c). Optically pure alpha amino esters 4 (preferably the (S)-isomers) can be obtained i) by chromatographic separation into antipodes using a preparative chiral HPLC column or ii) by catalytic hydrogenation of enamine carbamates 3 in the presence of rhodium catalysts carrying chiral ligands like 1,2-bis[(2S,5S)-2,5-diethylphospholano]-benzene [compare J. Am. Chem. Soc. (2000), 122(16), 3830-3838] in solvents like methanol followed by removal of the Z-protective group using standard reaction conditions like hydrogenolysis with the help of a palladium catalyst. Alpha amino esters 4 are then converted into enamines 5 by reaction with suitable ketones in inert solvents like toluene, optionally in the presence of a catalyst like p-toluene sulfonic acid, and at reflux temperature. In case 2-benzoyl-cyclohexanone is used as ketone component in an inert solvent like anisole in the presence of Pd on charcoal at temperatures around 180xc2x0 C., enamine-formation is followed by aromatization (step d). Enamine-esters rac-5 or (S)-5 can optionally be saponified to acids rac-6 or (S)-6 using standard conditions of alkaline hydrolysis (step e). 
Homochiral alpha alkoxy phenyl-propionic acid compounds of formula 8 can be prepared according to the method depicted in scheme 4 or by analogous methods known in the art.
The well known chiral auxiliary 2 [(S)-4-benzyl-oxazolidin-2-one] is condensed with an alkoxy-acetyl chloride 1 in the presence of a strong base like n-butyl lithium in an inert solvent like tetrahydrofuran at temperatures around xe2x88x9278xc2x0 C. to produce building block 3 (step a). The latter is then treated according to literature precedence [Tetrahedron Asymmetry (1999), 10, 1353-1367] with dibutylboron-triflate and a tertiary amine like triethylamine in dichloromethane to generate the corresponding boron enolate, which is subsequently reacted at low temperatures with benzaldehydes 4 (compounds 5 in scheme 1) resulting in compounds 5 (step b). In compounds 5, one of all four possible stereoisomers is strongly predominating (stereochemistry as indicated without rigorous proof). The benzylic hydroxy group is then reductively removed as described for the conversion of compounds 8 to compounds 9 in scheme 1 to yield the penultimate intermediate 6 (step c). Esters 7 or acid compounds 8 can finally be obtained without racemization by careful alcoholysis with a sodium alcoholate in the corresponding alcohol as solvent or in solvents like tetrahydrofuran or dioxane at temperatures around 0xc2x0 C. (step d) or by careful hydrolysis with diluted NaOH in tetrahydrofuran/water at 0xc2x0 C. (step e). The optical purity of compounds 7 and 8 can be determined by chiral HPLC or by 1H-NMR-spectroscopy in the presence of a chiral solvent like 1-(9-anthryl)-2,2,2-trifluoro-ethanol and has been found high in all cases exemplified.
Phenols 1 and/or aldehydes 6 (scheme 1), phenols 1 and/or protected phenols 2 and/or protected aldehydes 3 (scheme 2) and oxazoles 2 (scheme 1) are known or can be synthesized by methods known in the art. Examples for possible syntheses of these key intermediates are given in schemes 5-12.
4-Hydroxy-benzofurans 5 [Synthetic Communications (1986), 16(13), 1635-1640; Helvetica Chimica Acta (1933), 16, 121-129] and 4-hydroxy-benzothiophenes 8 [Jpn. Kokai Tokkyo Koho (2001), 2001048876A2] are known. Thus, cyclohexane-1,3-diones 1 carrying variable substituents R6 at the 5-position can be reacted with bromo-pyruvic acid in methanol in the presence of a base like potassium hydroxide at temperatures between 0xc2x0 C. and the reflux temperature of methanol followed by treatment with hydrochloric acid at around 100xc2x0 C. to give furan-carboxylic acids 3 (step a). Treatment of these furan-carboxylic acids 3 in an inert solvent like decahydro-naphthalene in the presence of a hydrogen acceptor like dodecene and palladium on carbon, preferably at reflux, provides carboxy-benzofurans 4 (step b), which are decarboxylated to benzofurans 5, e.g. by using copper powder in quinoline at temperatures between 200xc2x0 C. and 240xc2x0 C. (step c). Treatment of 2-thiophenecarbaldehyde 6 with suitable vinyl-lithium- or vinyl-magnesium-derivatives in solvents like tetrahydrofuran or 1,2-dimethoxy-ethane, preferably in a temperature range between xe2x88x9278xc2x0 C. and room temperature, followed by in situ treatment with acetic anhydride yields thiophenes 7 with variable substitution R6 (step d). Treatment of thiophenes 7 with carbon monoxide, preferably at a pressure of 20 to 60 bar, a palladium catalyst like palladium acetate, a phosphine like triphenylphosphine, in solvent mixtures which may typically contain acetic anhydride, triethylamine, toluene or tetrahydrofuran, preferably in a temperature range between 100xc2x0 C. to 160xc2x0 C., affords after saponification of the acetate function, benzothiophenes 8 (step e). 
2-Hydroxy-3-methoxy-benzaldehyde 1, optionally substituted with bromine in position 5, can be transformed into benzo[b]thiophen-7-ol 6 or 5-bromo-benzo[b ]thiophen-7-ol 6. This sequence can be carried out in analogy to the method described in J. Chem. Soc., Perkin Trans. 1 1983(12), 2973-7. For the transformation of 2-hydroxy-3-methoxy-benzaldehyde into benzo[b]thiophen-7-ol: treatment with N,N-dimethylthiocarbamoyl chloride in a solvent like tetrahydrofuran in the presence of an aqueous base like potassium hydroxide in water or in the presence of an organic base like diisopropyl-ethyl-amine, preferably at temperatures between 0xc2x0 C. and room temperature, generates thionocarbamates 2 (step a); thermal rearrangement of 2 without solvent or preferably in an inert solvent like diphenyl ether at temperatures between 200xc2x0 C. and 280xc2x0 C. leads to S-arylthiocarbamates 3 (step b); saponification in a solvent like an alcohol with a base like sodium or potassium hydroxide, preferably between room temperature and the reflux temperature of the solvents, leads then to thiophenols 4 (step c); reaction of thiophenols 4 with sodium chloroacetate in water or a water alcohol mixture in the presence of a base like sodium or potassium hydroxide in a temperature range between room temperature and the reflux temperature of the solvents produces then benzothiophene-carboxylic acids 5 (step d); decarboxylation, e.g. in quinoline in the presence of copper bronze at temperatures between 200xc2x0 C. and 240xc2x0 C., followed by cleavage of the methyl ether function, e.g. by treatment with aqueous hydrobromic acid in acetic acid at reflux, then finally yields benzo[b]thiophen-7-ols 6 (step e). 7-Hydroxy-benzofuran is known and commercially available [J. Med. Chem. (1987), 30(1), 62-7]. In a sequence similar to that described above, the 5-bromo-analogue can be prepared from 2-hydroxy-3-methoxy-benzaldehyde 1 by reaction with ethyl chloro-actetate in a solvent like N,N-dimethylformamide in the presence of a base like potassium carbonate at temperatures between 60xc2x0 C. and 120xc2x0 C. yielding benzofuran carboxylic acid 7 (step f). Decarboxylation as described above and ensuing ether cleavage, preferably with pyridine hydrochloride at temperatures around 200xc2x0 C., then leads to 5-bromo-7-hydroxy-benzofuran 8 (step g). 
1-Hydroxy-naphthalene 1 and 2,3-annelated phenols 2 with a ring size of 5, 6 and 7 are commercially available or known [see J. Am. Chem. Soc. (1988), 110(19), 6471-6480; U.S. Pat. No. 6,121,397; (2000) PCT Int. Appl. (1999) WO99/10339]. 3-Bromo-1-hydroxy-naphthalene 4, an intermediate carrying a functionality, which allows synthetic modifications at a later stage, can be prepared from 3-nitro-1-methoxy-naphthalene 3 [Monatsh. Chem. (1992), 123(6-7), 637-645] by well established procedures, i.e. reduction of the nitro function, e.g. by hydrogenation in the presence of a palladium catalyst, followed by diazotisation, Sandmeyer reaction and cleavage of the methyl ether function giving 3-bromo-1-hydroxy-naphthalene 4 (steps a, b, c). 2,3-Annelated carboxylic acids 5 are known, their 3-bromo analogues 6 are known or can be prepared by established methods of bromination of aromatic nuclei [J. Org. Chem. (1978), 43(11), 2167-70; Ger. Offen. (1977), DE 2633905] (step d). Such 3-bromo-benzoic acids can then be converted into the corresponding phenols 7 by known methods such as e.g. exhaustive reduction with borane to the corresponding alcohol, oxidation, e.g. by using Swern conditions (oxalyl chloride/dimethylsulfoxide/triethylamine in dichloromethane, xe2x88x9278xc2x0 C. to room temperature) to the corresponding alehyde, followed by Baeyer-Villiger oxidation with peracetic acid (40%) in acetic acid (steps e, f, g). 
Bromo-methoxy compound 1 characterized by an annelated hexahydropyran ring is known [Can. J. Chem. (1982), 60(16), 2093-8]. Cleavage of the methoxy ether function with pyridine hydrochloride at temperatures around 200xc2x0 C. leads to 3-bromo-phenol 2 (step a). The isomeric building block can be obtained as follows: Carboxylic acid 3 [U.S. (1999), U.S. Pat. No. 5,856,529 A] can be brominated to give the 3-bromo derivative 4 (step b) which can be transformed into phenol 5 by a sequence analogous to that described for the transformaton of the compounds 6 into compounds 7 in scheme 7 (steps c, d, e). 
3-Bromo-phenols 1, optionally carrying a protective function, can be converted in analogous phenols 2 carrying variable substiutents R6 by first transforming the bromo-compound into the corresponding aryl-lithium derivative (e.g. by using an alkyl lithium reagent in a solvent like tetrahydrofuran, preferably at a temperature around xe2x88x9278xc2x0 C.) and then quenching the latter with a variety of electrophiles using methods well known in the art (step a). For the synthesis of phenols (R6xe2x95x90OH), the aryl lithium compounds are reacted with trimethyl-borate at temperatures between xe2x88x9278xc2x0 C. and the reflux temperature of tetrahydrofuran, followed by oxidation with e.g. N-methyl morpholine N-oxide, preferably at the reflux temperature of tetrahydrofuran [compare Synlett 1995(09), 931-932]. These phenols 2 with R6 equal OH can then be transformed into the corresponding ether compounds by well known methods. 
Phenols 1, optionally carrying a protective function, can be further functionalized into phenols 2 carrying additional substutents R2 by known methods of electrophilic aromatic subsitution. In many cases, mixture of ortho/para-substitution-, and ortho/para-disubstitution-products will be formed in ratios depending on the precise reaction conditions. In such cases, the reaction conditions can be optimized in order to achieve the highest possible yield of mono-ortho product; optionally, product mixtures can also be separated into pure isomers by known methods such as silica gel chromatography (step a). 4-Formyl compounds 3 can be obtained from phenols 1, optionally carrying a protective function, by known formylation reactions such as the Vilsmeier formylation or by formylation with dichloromethyl methyl ether in the presence of titanium tetrachloride, preferably in dichloromethane at temperatures between xe2x88x9278xc2x0 C. and the reflux temperature of the solvent (step b). 4-Formyl compounds 3 can then again be used as starting materials for known methods of electrophilic aromatic subsitution leading to compounds 4 carrying an additional R2 substituent (step c). 
Aldehydes 1 are commercially available or known. They are condensed with diketo-monoximes 2 according to literature precedence (Diels, O.; Riley, K.; Chem Ber (1915), 48, 897) in the presence of a strong acid, typically HCl, in a polar solvent like ACOH to yield the oxazole-N-oxides 3 (step a). Subsequent treatment with POCl3 in dichloromethane under reflux provides the corresponding primary chlorides 4 (Goto, Y.; Yamazaki, M.; Hamana, M.; Chem Pharm Bull (1971), 19, 2050, step b). These intermediates are either used as such, transformed according to well established methods into the corresponding alcohols or activated alcohols like mesylates or tosylates or into the bromides or iodides, or finally further elaborated via SN2-reaction with NaCN to give, via nitrils 5 (step c), exhaustive hydrolysis (step d) and reduction (step e), e.g. with borane in tetrahydrofuran, the building blocks 7.
4-Chloromethyl-2-aryl or 2-heteroaryl-oxazoles 4 with R7 equal hydrogen are preferably prepared from the corresponding aryl or heteroaryl carboxamides and 1,3-dichloroacetone as described e.g. in Bioorg. Med. Chem. Lett. (2000), 10(17), 2041-2044. 
N-Acyl-glycine esters 1 are either commercially available, known, or can be prepared by standard operations of N-acylation. Mono-allylated esters 2 can easily be obtained by double deprotonation of 1 with a strong, non-nucleophilic base like LiHMDS in an aprotic solvent like THF, typically at xe2x88x9278xc2x0 C., followed by treatment with allyl bromide to produce selectively the C-alkylated products 2 (step a). Standard hydrolysis generates intermediate acids 3 (step b), which are then transformed, following well established literature precedence (J. Med. Chem. (1996), 39, 3897), into compounds 4 (step c). Ring-closure to the oxazole using trifluoro-acetic acid and trifluoro-acetic anhydride as reagents generates key intermediates 5 (step d), which, finally, are elaborated via hydroboration to the target alcohols 6, e.g. with 9-BBN in THF and ensuing oxidative work-up with H2O2 and NaOH (step e).
The following tests were carried out in order to determine the activity of the compounds of formula I.
Background information on the performed assays can be found in: Nichols JS et al. xe2x80x9cDevelopment of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domainxe2x80x9d, (1998) Anal. Biochem. 257:112-119.
Full-length cDNA clones for human PPARxcex1 and mouse PPARxcex3 were obtained by RT-PCR from human adipose and mouse liver cRNA, respectively, cloned into plasmid vectors and verified by DNA sequencing. Bacterial and mammalian expression vectors were constructed to produce glutathione-s-transferase (GST) and Gal4 DNA binding domain proteins fused to the ligand binding domains (LBD) of PPARxcex3 (aa 174 to 476) and PPARxcex1 (aa 167 to 469). To accomplish this, the portions of the cloned sequences encoding the LBDs were amplified from the full-length clones by PCR and then subcloned into the plasmid vectors pGEX4T-2(Pharmacia) and pFA-CMV(Stratagene). Final clones were verified by DNA sequence analysis.
Induction, expression, and purification of GST-LBD fusion proteins were performed in E. coli strain BL21(pLysS) cells by standard methods (Ref: Current Protocols in Molecular Biology, Wiley Press, edited by Ausubel et al.).
PPARxcex1 receptor binding was assayed in TKE10 (10 mM Tris-HCl, pH 8, 50 mM KCl, 2 mM EDTA, 0.1 mg/ml fatty acid free BSA and 10 mM DTT). For each 96 well 2.4 ug equivalent of GST-PPARxcex1-LBD fusion protein and radioligand, e.g. 40000 dpm 2(S)-(2-benzoyl-phenylamino)-3-{4-[1,1-ditritio-2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid, were incubated in 100 ul volume at RT for 2 hrs. Bound ligand was removed from unbound ligand by solid phase separation using MultiScreen plates (Millipore) filled with 80 ul of SG25 according to the manufacturer""s recommendations.
PPARxcex3 receptor binding was assayed in TKE50 (50 mM Tris-HCl, pH 8, 50 mM KCl, 2 mM EDTA, 0.1 mg/ml fatty acid-free BSA and 10 mM DTT). For each 96 well reaction an 140 ng equivalent of GST-PPARxcex3-LBD fusion protein was bound to 10 ug SPA beads (PharmaciaAmersham) in a final volume of 50 ul by shaking. The resulting slurry was incubated for 1 h at RT and centrifuged for 2 min at 1300 g. The supernatant containing unbound protein was removed and the semidry pellet containing the recptor-coated beads was resolved in 50 ul of TKE. For radioligand binding e.g. 10000 dpm 2(S)-(2-benzoyl-phenylamino)-3-{4-[1,1-ditritio-2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid in 50 ul were added, the reaction incubated at RT for 1 h and scintillation proximity counting performed. All binding assays were performed in 96 well plates and the amount of bound ligand measured on a Packard TopCount using OptiPlates (Packard). Nonspecific binding was determined in the presence of 10xe2x88x924 M unlabelled compound. Dose response curves were done in triplicates within a range of concentration from 10xe2x88x9210 M to 10xe2x88x924 M.
Baby hamster kidney cells (BHK21 ATCC CCL10) were grown in DMEM medium containing 10% FBS at 37xc2x0 C. in a 95% O2:5% CO2 atmosphere. Cells were seeded in 6 well plates at a density of 105 Cells/well and then batch-transfected with either the pFA-PPARxcex3-LBD or pFA-PPARxcex1-LBD expression plasmids plus the pFR-luc reporter plasmid (Stratagene) and an expression plasmid encoding the secretable form of alkaline phosphatase (SEAP) as a normalization control. Transfection was accomplished with the Fugene 6 reagent (Roche Molecular Biochemicals) according to the suggested protocol. Six hours following transfection, the cells were harvested by trypsinization and seeded in 96 well plates at a density of 104 cells/well. After 24 hours to allow attachment of cells, the medium was removed and replaced with 100 ul of phenol red-free medium containing the test substances or control ligands (final. 0.1% DMSO). Following incubation of the cells for 24 hours with substances, 50 ul of the supernatant was recovered and analyzed for SEAP activity (Roche Molecular Biochemicals). The remainder of the supernatant was discarded, 50 ul PBS was added per well followed by one volume of Luciferase Constant-Light Reagent (Roche Molecular Biochemicals) to lyse the cells and initiate the luciferase reaction. Luminescence for both SEAP and luciferase was measured in a Packard TopCount. Luciferase activity was normalized to the SEAP control and transcriptional activation in the presence of a test substance was expressed as fold-activation over cells incubated in the absence of the substance. EC50 values were calculated using the XLfit program (ID Business Solutions Ltd. UK).
The compounds of the present invention exhibit IC50 values of 0.1 nM to 50 xcexcM, preferably 1 nM to 10 xcexcM, paricularly 1-3500 nM, more preferred 1-500 nM, for PPARxcex1 and PPARxcex3. The compounds further exhibit EC50 values of 0.1 nM to 50 xcexcM, preferably 1 nM to 10 xcexcM, more preferably 1-3500 nM, particularly 1-500 nM, for PPARxcex1 and PPARxcex3.
The compounds of formula I and their pharmaceutically acceptable salts and esters can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.
The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and their pharmaceutically acceptable, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 mg to about 1000 mg, especially about 1 mg to about 100 mg, comes into consideration. Depending on the dosage it is convenient to administer the daily dosage in several dosage units.
The pharmaceutical preparations conveniently contain about 0.5-500 mg, preferably 0.5-100 mg, of a compound of formula I.
The following Examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.